Department of Oncology, University of Torino School of Medicine, 10060 Candiolo, Torino, Italy.
Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy.
Sci Transl Med. 2018 May 23;10(442). doi: 10.1126/scitranslmed.aah4807.
Vascular normalizing strategies, aimed at ameliorating blood vessel perfusion and lessening tissue hypoxia, are treatments that may improve the outcome of cancer patients. Secreted class 3 semaphorins (SEMA3), which are thought to directly bind neuropilin (NRP) co-receptors that, in turn, associate with and elicit plexin (PLXN) receptor signaling, are effective normalizing agents of the cancer vasculature. Yet, SEMA3A was also reported to trigger adverse side effects via NRP1. We rationally designed and generated a safe, parenterally deliverable, and NRP1-independent SEMA3A point mutant isoform that, unlike its wild-type counterpart, binds PLXNA4 with nanomolar affinity and has much greater biochemical and biological activities in cultured endothelial cells. In vivo, when parenterally administered in mouse models of pancreatic cancer, the NRP1-independent SEMA3A point mutant successfully normalized the vasculature, inhibited tumor growth, curbed metastatic dissemination, and effectively improved the supply and anticancer activity of chemotherapy. Mutant SEMA3A also inhibited retinal neovascularization in a mouse model of age-related macular degeneration. In summary, mutant SEMA3A is a vascular normalizing agent that can be exploited to treat cancer and, potentially, other diseases characterized by pathological angiogenesis.
血管正常化策略旨在改善血管灌注并减轻组织缺氧，这些治疗方法可能会改善癌症患者的预后。分泌的 III 类信号素（SEMA3）被认为可以直接与神经纤毛蛋白（NRP）共受体结合，而 NRP 共受体又与神经纤毛蛋白（plexin，PLXN）受体信号转导相关联，从而有效地调节肿瘤血管。然而，SEMA3A 也被报道通过 NRP1 触发不良反应。我们合理设计并生成了一种安全的、可通过注射给药的、不依赖 NRP1 的 SEMA3A 点突变体同工型，与野生型相比，其与 PLXNA4 的结合亲和力为纳摩尔级，并且在培养的内皮细胞中具有更强的生化和生物学活性。在体内，当在胰腺癌的小鼠模型中通过注射给药时，不依赖 NRP1 的 SEMA3A 点突变体成功地使血管正常化，抑制肿瘤生长，抑制转移扩散，并有效地改善了化疗的供应和抗癌活性。突变型 SEMA3A 还抑制了年龄相关性黄斑变性小鼠模型中的视网膜新生血管形成。总之，突变型 SEMA3A 是一种血管正常化剂，可用于治疗癌症，以及可能用于治疗其他以病理性血管生成为特征的疾病。
